Certain efforts in precision cancer medicine are predicated on the identification of “actionable oncogene mutations”, under the assumption that their pharmacological inhibition will elicit oncogene addiction1. Despite integration of this methodology into clinical cancer care, challenges remain.
First, stratification of cancer patients based on actionable mutations2 has shown that certain adult malignancies lack actionable alterations altogether or present with mutations in undruggable oncogenes (e.g. RAS/MYC family proteins) or in genes of uncharacterized therapeutic value3. Additionally, while oncogene targeting can achieve initial responses, these can be followed by rapid relapse due to emergence of drug-resistance4,5. Also, analysis of hundreds of cell lines and compounds shows that, with the exception of a handful of well-characterized targets (e.g., ERBB2, EGFR, mTOR, ALK, MET, PI3K and ESR1, among others), single-gene mutations can be poor overall predictors of sensitivity to inhibitors of the corresponding protein6.
Drug sensitivity represents a multifactorial, polygenic (i.e., complex) phenotype, highlighting the need for novel approaches that complement and extend the actionable alteration paradigm. Accordingly, there is a need for a novel approach that complements and extends the actionable alteration paradigm.